Prenatal substance exposure continues to be a major public health problem that affects millions of children and places enormous financial and social burdens on society. Little is known about the effects of prenatal cocaine exposure on psychological, developmental, medical or physical outcomes in children entering adolescence. The Maternal Lifestyle Study (MLS) is an interagency collaboration involving the National Institute of Child Health and Human Development and the National Institute on Drug Abuse. MLS is being conducted in four academic centers: The University of Miami, University of Tennessee at Memphis, Wayne State University and Brown University. MLS is the largest clinical prospective longitudinal study to date of prenatal drug exposure and child outcome. The follow-up cohort includes 658 exposed and 730 comparison children who have been studied through 9 years of age with 75% retention. The MLS study involves a unique population given its multi-site component, racial diversity, and extensive long-term follow up. One aim is to determine if prenatal cocaine or other prenatal drug exposure results in adverse psychological and developmental outcomes at 12-15 years. These outcomes include substance use (early substance use onset, smoking, alcohol consumption and substance abuse and addiction), academic and cognitive deficits (e.g., poor school performance), physiological reactivity, antisocial behavior (e.g. delinquency), psychopathology, risk taking behavior (e.g., adolescent pregnancy, sexually transmitted diseases). The role of protective factors such as positive parenting and peer relationships will also be investigated. A second aim is to determine the effects of prenatal cocaine exposure on physical and medical outcomes at 12-15 years. These outcomes include physical growth and medical illness, including hypertension, obesity and metabolic disorder, which may have their origins in fetal life, and may be related the impact of drug exposure on fetal growth. Additional outcomes include structural teratogenic effects (dysmorphology), and neurological disorders. In addition to being a study of prenatal cocaine exposure, MLS is also a study of children growing up in adverse conditions, providing information on development in typically developing children and children at risk. A thorough understanding of the consequences of prenatal cocaine exposure and associated maternal lifestyles is necessary to the development of treatment and public policy initiatives.